Studies of families with neurofibromatosis type 1 (NF1) have demonstrated that the severity of this disease depends on modifier genes in the individuals. We are using a mouse model of the malignancies associated with NF1 in which the Nf1 and p53 gene are mutated on the same chromosome and screening for modifier genes in different strains of mice. We have recently identified a region responsible for resistance to developing malignant peripheral nerve sheath tumors in one strain of mice, and another region responsible for susceptibility to astrocytoma. We are working to identify candidate modifier genes within these regions that can be tested for their role in tumorigenesis in our mouse model and then in human cancers.